1.以一鍋化三步進行分子內克腦文蓋爾環化形成香豆素連接苯並咪唑的多樣性導向合成 2.多分子反應合成2-氮雜-7-芳基吡咯烷啶生物鹼衍生物

Abstract

第一部分：經由一鍋化三步合成的方式得到最終產物3-(1-propyl-1H-benzo[d]imidazol-2-yl)-2H-chromen-2-one，利用 2-cyano-N-(2-(propylamino)phenyl)acetamide化合物11在對甲苯磺酸催化下進行分子內環化(intramolecular cyclization)形成 2-(1-propyl-1H-benzo[d]imidazol-2-yl)acetonitrile化合物12，再加入過當量的三乙胺進行克腦文蓋爾縮合反應(Knoevenagel condensation reaction)形成中間體亞胺化合物14，最後加入1N HCl進行亞胺水解得到產物15，此部分的結果已發表在ACS Comb. Sci,.2017, 19(4), 271-275。 第二部分：在第一部分研究中得到的化合物12，可進一步合成多雜環結構，增加其生物活性及多樣性，如: 吡唑(pyrazole)。將化合物12、苯甲醛18以及哌啶(piperidine)在甲苯溶液下反應形成烯類化合物23，再與苯肼化合物17及碳酸銫在乙醇溶液下反應可得產物 1H-苯並[d]咪唑-1,3-二苯基-1H-吡唑-5-胺(1H-benzo[d]imidazole-1,3-diphenyl-1H-pyrazol-5-amine) 22。 第三部分：利用一鍋化合成單一非鏡像光學異構物的2-氮雜-7-芳基吡咯烷生物鹼衍生物31。首先以L-酯基胺基酸32與異硫氰酸酯33在室溫下反應30分鐘形成中間體5-芳基硫代海因(5-aryl thiohydantain)30，再依序加入丙二腈、苯甲醛以及哌啶，室溫下反應12小時後可得產物2-氮雜-7-芳基吡咯烷啶(2-aza-7-arylpyrrolizidine) 31。

First part:One-pot, three step synthesis of 3-(1-propyl-1H- benzo[d]imidazol-2-yl)-2H-chromen-2-one, using 2-cyano-N-(2-(propylamino)phenyl)acetamide compound 11 under p-toluene sulfonic acid catalyst to undergo intramolecular cyclization to form 2-(1-propyl-1H-benzo[d]imidazol-2-yl)acetonitrile compound 12, then add proper triethylamine to undergo Knoevenagel condensation reaction to get intermediate 14, and finally add 1N HCl to provide compound 15. Second part: Compounds 12 obtained in the first part of the study can further synthesize polycyclic structures to increase their biological activity and diversity, such as pyrazole. The compound 12, benzaldehyde 18 and piperidine are reacted in toluene to form the olefinic compound 23 and reacted with the phenylhydrazine compound 17 and cesium carbonate in an ethanol solution to give the product 1H-benzo [d] imidazole-1,3-diphenyl-1H-pyrazol-5-amine. Part 3: Synthesis of 2-aza-7-arylpyrrolidine alkaloid derivatives using a single non-mirror optical isomer. The intermediate 5-aryl thiohydantain 30 was first reacted with L-ester-based amino acid 32 and isothiocyanate 33 at room temperature for 30 minutes, followed by the addition of malononitrile , Benzaldehyde and piperidine at room temperature for 12 hours to give the product 2-aza-7-arylpyrrolididine 31.